Induction and Expression of Heparin-Binding EGF-Like Growth Factor in Human Pancreatic Cancer

Kobrin, Michael S.; Funatomi, Hitoshi; Friess, Helmut; Büchler, Markus W.; Stathis, Peter; Korc, Murray

doi:10.1006/bbrc.1994.2131

Cited by 106 publications

(78 citation statements)

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“…The effect of heparin on EGF-stimulated proliferation of pancreatic cancer cells is consistent with another study which showed that heparin sulphate does not affect the TGFα-stimulated clonal growth of human keratinocytes (Cook et al, 1991). Other investigators have provided evidence to suggest that HB-EGF-like growth factor and amphiregulin may play important roles in growth regulation of human pancreatic cancer Schuger et al, 1996;Kobrin et al, 1994;Funatomi et al, 1997). Since heparin had no effect on EGF-stimulated proliferation in the present study, it is likely that exogenous heparin interacts with the basic amino acid residues in the amino-terminal regions of endogenous amphiregulin and/or HB-EGF (Schuger et al, 1996) thus preventing productive interactions between these ligands and the EGF receptor.…”

Section: Discussionsupporting

confidence: 71%

Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions

et al. 2001

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In-vitro and in-vivo studies have shown that autocrine growth factors and receptors are frequently expressed in human malignancies. Few of these studies, however, provide evidence that the identified autocrine pathway is functional. In this study, a functional autocrine growth pathway in pancreatic cancer has been identified using an in-vitro cell culture system. When pancreatic cancer cells were grown without change of medium, proliferation was greater than when either medium was replaced frequently (HPAF, CAPAN-2, PANC-1 or SW1990) or cells were grown in the presence of the EGF receptor tyrosine kinase inhibitor AG1478 or the MEK inhibitor PD098059 (HPAF or CAPAN-2). Activity of extracellular-regulated kinases (ERK) 1 and 2 and c- jun and c- fos mRNA levels were significantly elevated in CAPAN-2 cells cultured continuously in serum-free medium. Collectively, the observations indicate that the EGF receptor and the ERK MAP kinase pathway mediate autocrine signals. In contrast to previous reports, the GRP and IGF-I receptors were shown not to be required for autocrine effects on pancreatic cancer cell proliferation. Autocrine stimulation of the EGF receptor can contribute to sustained mitogenic activity and proliferation of pancreatic cancer cells. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionsupporting

confidence: 71%

Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions

et al. 2001

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“…Additionally, HB-EGF has been shown to up-regulate the transcription of its own gene (14). Thus it was possible that the IGF-1R-mediated increase in HB-EGF mRNA levels was in fact occurring via cleavage of HB-EGF already present at the cell surface and subsequent activation of the EGFR.…”

Section: Tigr-mediated Up-regulation Of Hb-egf Gene Transcription Doementioning

confidence: 99%

“…Since its discovery, the mitogenic properties of HB-EGF have been implicated in several processes, including wound healing, liver regeneration, and cancer (14,(22)(23)(24). It is synthesized as a transmembrane precursor (also known as the diphtheria toxin receptor (25)) which is cleaved to release mature soluble HB-EGF.…”

Section: Fig 4 Signaling Pathways To Hb-egf Gene Expression In 3t3-mentioning

confidence: 99%

Microarray Analysis of Insulin and Insulin-like Growth Factor-1 (IGF-1) Receptor Signaling Reveals the Selective Up-regulation of the Mitogen Heparin-binding EGF-like Growth Factor by IGF-1

Mulligan

Rochford

Denyer

et al. 2002

Journal of Biological Chemistry

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Insulin and insulin-like growth factor-1 (IGF-1) act through highly homologous receptors that engage similar intracellular signaling pathways, yet these hormones serve largely distinct physiological roles in the control of metabolism and growth, respectively. In an attempt to uncover the molecular mechanisms underlying their divergent functions, we compared insulin receptor (IR) and IGF-1 receptor (IGF-1R) regulation of gene expression by microarray analysis, using 3T3-L1 cells expressing either TrkC/IR or TrkC/IGF-1R chimeric receptors to ensure the highly selective activation of each receptor tyrosine kinase. Following stimulation of the chimeric receptors for 4 h, we detected 11 genes to be differentially regulated, of which 10 were up-regulated to a greater extent by the IGF-1R. These included genes involved in adhesion, transcription, transport, and proliferation. The expression of mRNA encoding heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen, was markedly increased by IGF-1R but not IR activation. This effect was dependent on MAPK, but not phosphatidylinositol 3-kinase, and did not require an autocrine loop through the epidermal growth factor receptor. HB-EGF mitogenic activity was detectable in the medium of 3T3-L1 preadipocytes expressing activated IGF-1R but not IR, indicating that the transcriptional response is accompanied by a parallel increase in mature HB-EGF protein. The differential abilities of the IR and IGF-1R tyrosine kinases to stimulate the synthesis and release of a growth factor may provide, at least in part, an explanation for the greater role of the IGF-1R in the control of cellular proliferation.

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“…38,41 Cell culture experiments with PCCL have shown increased cancer cell growth under stimulation with each of those ligands. 39,[42][43][44] Analysis of the other receptors in PDAC has demonstrated increased expression of ErbB2 and ErbB3 and decreased expression of ErbB4. [45][46][47][48] Increased expression for ErbB2 and ErbB3 but not ErbB4 correlates with an advanced disease state and increased invasiveness 27,46,47,49 ( Fig.…”

mentioning

confidence: 99%

Expression and differential signaling of heregulins in pancreatic cancer cells

Kolb

Kleeff

Arnold

et al. 2006

Intl Journal of Cancer

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The EGF family of ligands and receptors plays an important role in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and contributes to its aggressiveness. A number of molecular approaches have been developed to block these pathways, and studies have already proven the clinical benefit of this concept in PDAC. In the present study, we sought to determine the potential role of heregulins (HRGs), a family of EGF-like growth factors, in PDAC. Quantitative RT-PCR analysis revealed that HRGs as well as its signaling ErbB receptors were present in 4 of 4 human pancreatic cancer cell lines (PCCL). HRG-b1 stimulated the growth of 3 of 4 PCCL, whereas HRG-a1 inhibited cell growth in 3 of 4 cell lines. Responses towards HRGs could in part be predicted by ErbB2 and ErbB3 expression levels. HRGs induced phosphorylation of different ErbB receptors as well as activation of MAPK, p38MAPK, JNK and PI3K in a cell-and ligand-specific manner. In vivo, HRG was upregulated in pancreatic cancer tissues and localized predominantly in the cancer cells. High HRG-b levels but not HRG-a levels were associated with decreased patient survival. In conclusion, HRG is expressed by pancreatic cancer cells and influences pancreatic cancer cell growth and patient survival. ' 2006 Wiley-Liss, Inc.

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Induction and Expression of Heparin-Binding EGF-Like Growth Factor in Human Pancreatic Cancer

Cited by 106 publications

References 0 publications

Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions

Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions

Microarray Analysis of Insulin and Insulin-like Growth Factor-1 (IGF-1) Receptor Signaling Reveals the Selective Up-regulation of the Mitogen Heparin-binding EGF-like Growth Factor by IGF-1

Expression and differential signaling of heregulins in pancreatic cancer cells

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